Pyridin-2-one compounds and their use as modulators of the dopamine D3 receptor

ABSTRACT

The invention relates to pyridin-2-one compounds of general formula (I) 
                         
in which
     A represents a 4- to 6-membered hydrocarbon chain that can have 1 or 2 methyl groups as substituents, wherein 1 or 2 carbon atoms can be replaced by oxygen, a carbonyl group or sulfur, and the hydrocarbon chain can have a double bond or a triple bond;   R 1 , R 2 , R 3  and R 4  have the meanings as cited in the claims and in the description.   

     The invention also relates to the tautomers of compounds I and the physiologically acceptable salts of the compounds I and their tautomers. 
     The invention also relates to the use of these compounds for treating diseases that respond to the influence of dopamine D 3  receptor antagonists or agonists.

This application is a 371 of PCT/EP2005/006001 filed Jun. 3, 2005.

The present invention relates to novel pyridin-2-one compounds of thegeneral formula I. These compounds have valuable therapeutic propertiesand are suitable in particular for the treatment of disorders whichrespond to modulation of the dopamine D₃ receptor.

Neurons receive their information inter alia via G protein-coupledreceptors. There are numerous substances which exert their effect viathese receptors. One of these is dopamine. Confirmed findings about thepresence of dopamine and its physiological function as neurotransmitterhave been published. Disturbances in the dopaminergic transmitter systemresult in disorders of the central nervous system which include, forexample, schizophrenia, depression or Parkinson's disease. These andother disorders are treated with medicaments which interact with thedopamine receptors.

Until 1990, two subtypes of dopamine receptors were clearly definedpharmacologically, namely the D₁ and D₂ receptors. More recently, athird subtype has been found, namely the D₃ receptor, which appears tomediate some effects of antipsychotics and antiparkinsonian drugs (J. C.Schwartz et al., The Dopamine D₃ Receptor as a Target forAntipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. RavenPress, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging1998, 12, 495-514, J. N. Joyce, Pharmacology and Therapeutics 2001, 90,pp. 231-259 “The Dopamine D₃-Receptor as a Therapeutic Target forAntipsychotic and Antiparkinsonian Drugs”).

Dopamine receptors are now divided into two families. Firstly the D₂group consisting of D₂, D₃ and D₄ receptors, and secondly the D₁ groupconsisting of D₁ and D₅ receptors. Whereas D₁ and D₂ receptors arewidespread, the expression of D₃ receptors by contrast appears to beregioselective. Thus, these receptors are preferentially found in thelimbic system, the projecting regions of the mesolimbic dopamine system,especially in the nucleus accumbens, but also in other regions such asamygdala. Because of this comparatively regioselective expression, D₃receptors are regarded as a target with few side effects, and it isassumed that a selective D₃ ligand ought to have the properties of knownantipsychotics but not their dopamine D₂ receptor-mediated neurologicalside effects (P. Sokoloff et al., Localization and Function of the D₃Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P.Sokoloff et al. Molecular Cloning and Characterization of a NovelDopamine Receptor (D₃) as a Target for Neuroleptics, Nature, 347, 146(1990)).

Pyridinone compounds having dopamine D₃ receptor affinity are disclosedin WO 96/02246. These compounds exhibit good affinities for the D₃receptor. They are therefore proposed for the treatment of disorders ofthe central nervous system. However, the selectivity in relation toother receptors is unsatisfactory.

The invention is therefore based on the object of providing compoundswhich act as selective dopamine D₃ receptor ligands. This object isachieved by pyridin-2-one compounds of the general formula I

in which

-   A is a 4- to 6-membered hydrocarbon chain which may have 1 or 2    methyl groups as substituents, in which 1 or 2 carbon atoms may be    replaced by oxygen, a carbonyl group or sulfur, and in which the    hydrocarbon chain may have a double bond or a triple bond;-   R¹, R² are independently of one another hydrogen, CN, NO₂, halogen,    OR⁵, NR⁶R⁷, C(O)NR⁶R⁷, O—C(O)NR⁶R⁷, SR⁸, SOR⁸, SO₂R⁸, SO₂NR⁶R⁷,    COOR⁹, O—C(O)R¹⁰, COR¹⁰, C₁-C₆-alkyl, C₁-C₆-haloalkyl,    C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkenyl, C₃-C₆-cycloalkyl,    -   4- to 6-membered heterocyclyl having 1, 2 or 3 heteroatoms        selected from O, S and N, which may have 1, 2 or 3 substituents        which are selected independently of one another from        C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, CN, OH, C₁-C₂-fluoroalkyl or        halogen, phenyl which may have 1, 2 or 3 substituents which are        selected independently of one another from C₁-C₄-alkyl,        C₁-C₄-alkoxy, NR⁶R⁷, OH, CN, C₁-C₂-fluoroalkyl or halogen,        C₁-C₆-alkyl which has a substituent which is selected from OR⁵,        NR⁶R⁷, C(O)NR⁶R⁷, O—C(O)NR⁶R⁷, SR⁸, SOR⁸, SO₂R⁸, SO₂NR⁶R⁷,        COOR⁹, O—C(O)R¹⁰, COR¹⁰, C₃-C₆-cycloalkyl, 5- or 6-membered        heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and        N, and phenyl, where phenyl and heterocyclyl may have 1, 2 or 3        substituents which are selected independently of one another        from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, CN, OH, C₁-C₂-fluoroalkyl        or halogen,    -   C₂-C₆-alkenyl which has a substituent selected from OR⁵, NR⁶R⁷,        C(O)NR⁶R⁷, O—C(O)NR⁶R⁷, SR⁸, SOR⁸, SO₂R⁸, SO₂NR⁶R⁷, COOR⁹,        O—C(O)R¹⁰, COR¹⁰, C₃-C₆-cycloalkyl, 5- or 6-membered        heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and        N, and phenyl, where phenyl and heterocyclyl in turn may have 1,        2 or 3 substituents which are selected independently of one        another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, OH, CN,        C₁-C₂-fluoroalkyl or halogen;-   R³, R⁴ are independently of one another OR⁵, NR⁶R⁷, CN, C₁-C₆-alkyl    which is optionally substituted one or more times by OH,    C₁-C₄-alkoxy, halogen or phenyl which in turn may have 1, 2 or 3    substituents selected from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, OH, CN,    C₁-C₂-fluoroalkyl or halogen, or C₂-C₆-alkenyl, C₂-C₆-alkynyl,    C₃-C₆-cycloalkyl, C₄-C₁₀-bicycloalkyl, C₆-C₁₀-tricycloalkyl, where    the last 5 groups mentioned may optionally be substituted one or    more times by halogen or C₁-C₄-alkyl, or halogen, CN, C₁-C₄-alkoxy,    5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected    from O, S and N, and phenyl, where phenyl and heterocyclyl may    optionally have 1, 2 or 3 substituents which are selected    independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷,    CN, C₁-C₂-fluoroalkyl and halogen;-   R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are independently of one another H,    C₁-C₆-alkyl which is optionally substituted by OH, C₁-C₄-alkoxy or    phenyl which in turn may have 1, 2 or 3 substituents selected from    C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, OH, CN, C₁-C₂-fluoroalkyl or    halogen, or C₁-C₆-haloalkyl or phenyl which in turn may have 1, 2 or    3 substituents selected from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, OH,    CN, C₁-C₂-fluoroalkyl or halogen, where-   R⁷ may also be a COR¹¹ group, and where-   R⁶ with R⁷ may also, together with the nitrogen to which they are    bonded, form a 4-, 5- or 6-membered, saturated or unsaturated    heterocycle which may have a further heteroatom selected from O, S    and NR¹² as ring member, where R¹² is hydrogen or C₁-C₄-alkyl, and    which may be substituted by 1, 2, 3 or 4 alkyl groups; and-   R¹¹ is hydrogen, C₁-C₄-alkyl or phenyl which is optionally    substituted by 1, 2 or 3 radicals which are selected independently    of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, CN,    C₁-C₂-fluoroalkyl or halogen;    and the tautomers of the compounds I, the physiologically acceptable    salts of the compounds I and the physiologically acceptable salts of    the tautomers of the compounds I.

The present invention therefore relates to the compounds of the generalformula I, their tautomers and the physiologically tolerated salts ofthe compounds I and the physiologically acceptable salts of thetautomers of I.

The present invention also relates to the use of compounds of thegeneral formula I and of the tautomers, and to the use of thephysiologically acceptable salts of the compounds I and of the tautomersfor producing a pharmaceutical composition for the treatment ofdisorders which respond to influencing by dopamine D₃ receptorantagonists or agonists.

The disorders which respond to influencing by dopamine D₃ receptorantagonists or agonists include in particular disorders and conditionsof the central nervous system, especially affective disorders, neuroticdisorders, stress disorders and somatoform disorders and psychoses,specifically schizophrenia and depression and additionally renalfunction disorders, especially renal function disorders caused bydiabetes mellitus (see WO 00/67847).

The aforementioned indications are treated by using according to theinvention at least one compound of the general formula I, a tautomer ofI, a physiologically acceptable salt of a compound I or a salt of atautomer of I. If the compounds of the formula I have one or morecenters of asymmetry, it is also possible to employ mixtures ofenantiomers, especially racemates, mixtures of diastereomers, mixturesof tautomers, but preferably the respective substantially pureenantiomers, diastereomers and tautomers.

Compounds of the formula I which may in particular be in the form oftautomers are those in which one or both of the radicals R¹ or R² is OHor NHR⁶ in which R⁶ has the aforementioned meanings.

It is likewise possible to use physiologically acceptable salts of thecompounds of the formula I and of the tautomers of I, especially acidaddition salts with physiologically tolerated acids. Examples ofsuitable physiologically tolerated organic and inorganic acids arehydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,C₁-C₄-alkylsulfonic acids such as methanesulfonic acid, aromaticsulfonic acids such as benzenesulfonic acid and toluenesulfonic acid,oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid,adipic acid and benzoic acid. Further acids which can be used aredescribed in Fortschritte der Arzneimittelforschung, volume 10, pages224 et seq., Birkhäuser Verlag, Basle and Stuttgart, 1966.

Halogen here and hereinafter is fluorine, chlorine, bromine or iodine.

C_(n)-C_(m)-Alkyl (also in radicals such as alkoxy, alkoxyalkyl,alkylthio, alkylamino, dialkylamino, alkylcarbonyl etc.) means astraight-chain or branched alkyl group having n to m carbon atoms, e.g.1 to 6 and in particular 1 to 4 carbon atoms. Examples of an alkyl groupare methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl,tert-butyl, n-pentyl, 2-pentyl, neopentyl, n-hexyl and the like.

The alkyl group may, unless the contrary is indicated, have one or moresubstituents which are selected independently of one another from OH,C₁-C₄-alkoxy, halogen and phenyl. In the case of a halogen substituent,the alkyl group may comprise in particular 1, 2, 3 or 4 halogen atomswhich may be located on one or more C atoms, preferably in the α or ωposition. Groups of this type are also referred to hereinafter ashaloalkyl. A preferred haloalkyl is C₁-C₂-fluoroalkyl orC₁-C₂-fluorochloroalkyl, in particular CF₃, CHF₂, CF₂Cl, CH₂F, CH₂CF₃.

In the case of hydroxy-substituted alkyl, the alkyl group has inparticular one hydroxy group, such as, for example, hydroxymethyl,2-hydroxyeth-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl,1-hydroxyprop-2-yl, 2-hydroxybut-1-yl, 3-hydroxybut-1-yl,4-hydroxybut-1-yl, 1-hydroxybut-2-yl, 1-hydroxybut-3-yl,2-hydroxybut-3-yl, 1-hydroxy-2-methylprop-3-yl,2-hydroxy-2-methylprop-3-yl or 2-hydroxymethylprop-2-yl, in particular2-hydroxyethyl.

In the case of alkoxy-substituted alkyl, the alkyl group has inparticular one alkoxy substituent. These radicals are referred to,depending on the number of carbon atoms, also asC_(n)-C_(m)-alkoxy-C_(n)-C_(m)-alkyl and are, for example,methoxymethyl, ethoxymethyl, 2-methoxyethyl, 1-methoxyethyl,2-ethoxyethyl, 1-ethoxyethyl, n-propoxymethyl, isopropoxymethyl,n-butoxymethyl, (1-methylpropoxy)methyl, (2-methylpropoxy)methyl,CH₂—OC(CH₃)₃, 2-(methoxy)ethyl, 2-(ethoxy)ethyl, 2-(n-propoxy)ethyl,2-(1-methylethoxy)ethyl, 2-(n-butoxy)ethyl, 2-(1-methylpropoxy)ethyl,2-(2-methylpropoxy)ethyl, 2-(1,1-dimethylethoxy)ethyl,2-(methoxy)propyl, 2-(ethoxy)propyl, 2-(n-propoxy)propyl,2-(1-methylethoxy)propyl, 2-(n-butoxy)propyl, 2-(1-methylpropoxy)propyl,2-(2-methylpropoxy)propyl, 2-(1,1-dimethylethoxy)propyl,3-(methoxy)propyl, 3-(ethoxy)propyl, 3-(n-propoxy)propyl,3-(1-methylethoxy)propyl, 3-(n-butoxy)propyl, 3-(1-methylpropoxy)propyl,3-(2-methylpropoxy)propyl, 3-(1,1-dimethylethoxy)propyl,2-(methoxy)butyl, 2-(ethoxy)butyl, 2-(n-propoxy)butyl,2-(1-methylethoxy)butyl, 2-(n-butoxy)butyl, 2-(1-methylpropoxy)butyl,2-(2-methylpropoxy)butyl, 2-(1,1-dimethylethoxy)butyl, 3-(methoxy)butyl,3-(ethoxy)butyl, 3-(n-propoxy)butyl, 3-(1-methylethoxy)butyl,3-(n-butoxy)butyl, 3-(1-methylpropoxy)butyl, 3-(2-methylpropoxy)butyl,3-(1,1-dimethylethoxy)butyl, 4-(methoxy)butyl, 4-(ethoxy)butyl,4-(n-propoxy)butyl, 4-(1-methylethoxy)butyl, 4-(n-butoxy)butyl,4-(1-methylpropoxy)butyl, 4-(2-methylpropoxy)butyl or4-(1,1-dimethylethoxy)butyl, preferably methoxymethyl, ethoxymethyl,2-methoxyethyl, 2-ethoxyethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl or3-(methoxy)propyl, 3-(ethoxy)propyl.

Cycloalkyl is in particular C₃-C₆-cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. Bicycloalkyl is a bicyclichydrocarbon radical having 4 to 10 C atoms such as bicyclo[2.1.0]pentyl,bicyclo[2.2.0]hexyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and thelike. Tricycloalkyl is a tricycloaliphatic radical having 6 to 10 carbonatoms, for example adamantyl.

The term “alkylene” comprises in principle straight-chain or branchedradicals having preferably 3 to 10 and particularly preferably 3 to 8carbon atoms, such as prop-1,2-ylene, prop-1,3-ylene, but-1,2-ylene,but-1,3-ylene, but-1,4-ylene, 2-methylprop-1,3-ylene, pent-1,2-ylene,pent-1,3-ylene, pent-1,4-ylene, pent-1,5-ylene, pent-2,3-ylene,pent-2,4-ylene, 1-methylbut-1,4-ylene, 2-methylbut-1,4-ylene,hex-1,3-ylene, hex-2,4-ylene, hex-1,4-ylene, hex-1,5-ylene,hex-1,6-ylene and the like. C₀-Alkylene is a single bond, C₁-alkylene ismethylene and C₂-alkylene is 1,1-ethylene or 1,2-ethylene.

C₂-C₆-Alkenyl is a mono unsaturated linear or branched hydrocarbonradical having 2, 3, 4, 5 or 6 C atoms, e.g. vinyl, allyl(2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl(2-methylprop-2-en-1-yl) and the like. C₃-C₄-Alkenyl is in particularallyl, 1-methylprop-2-en-1-yl, 2-buten-1-yl, 3-buten-1-yl or methallyl.

C₂-C₆-Haloalkenyl is an alkenyl group as defined above in which all orsome, e.g. 1, 2, 3, 4 or 5, of the hydrogen atoms are replaced byhalogen atoms, in particular by chlorine or fluorine.

C₂-C₆-Alkynyl is a hydrocarbon radical having 2, 3, 4, 5 or 6 C atomswhich has a triple bond, e.g. propargyl (2-propyn-1-yl),1-methylprop-2-yn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl,1-pentyn-3-yl etc.

5- or 6-membered heterocyclyl comprises both aromatic heterocyclyl(hetaryl or heteroaryl) and completely saturated or partiallyunsaturated heterocyclic radicals. Heterocyclyl has 1, 2 or 3heteroatoms selected from O, S and N, e.g. 1, 2 or 3 nitrogen atoms, 1or 2 oxygen atoms, or 1 oxygen atom and 1 or 2 nitrogen atoms or 1sulfur atom and 1 or 2 nitrogen atoms.

Heterocyclyl may be unsubstituted or have 1, 2 or 3 substituents whichare ordinarily selected from C₁-C₄-alkyl, C₁-C₄-alkoxy, OH, CN, NR⁶R⁷,C₁-C₂-fluoroalkyl and halogen.

Examples of saturated heterocyclyl are pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, oxolanyl, 1,3-dioxolanyl, 1,3- and1,4-dioxanyl, 1,3-oxothiolanyl, oxazolidinyl and the like.

Examples of “5- or 6-membered aromatic heterocyclic radicals” having 1,2 or 3 heteroatoms which are selected from O, S and N are in particularpyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, pyrrolyl,pyrazolyl, thienyl, furanyl, oxazolyl, thiazolyl, isoxazolyl,tetrazolyl, thiadiazolyl and triazolyl. These may have 1, 2 or 3 of theaforementioned substituents on the nitrogen atoms and on the carbonatoms. If one of the substituents is hydroxy, the radicals may also bein a tautomeric form with a carbonyl group.

In group A, the two bonding sites are preferably located in the 1,4position, 1,5 position or 1,6 position. Thus, in the compounds I, the2-pyridone residue is separated from the piperazine residue preferablyby a chain of 4, 5 or 6 atoms. 1 or 2 carbon atoms in the chain A may bereplaced by oxygen, sulfur or a carbonyl group. If one or two carbonatoms are replaced by oxygen or sulfur, these heteroatoms are preferablynot located at the ends of group A and are in particular not adjacent toone another. A may also have a double or triple bond and/or 1 or 2methyl groups and is preferably saturated. Examples of radicals A areCH₂—CH₂—CH₂—CH₂, CH₂—CH═CH—CH₂, CH₂—C≡C—CH₂, CH₂—CH(CH₃)—CH₂—CH₂, etc.

With a view to the use of the compounds of the invention as dopamine D₃receptor ligands, the variables A, R¹, R², R³ and R⁴ preferably haveindependently of one another the meanings indicated below:

-   R¹ halogen, OR⁵, NR⁶R⁷, C₁-C₄-alkyl which is optionally substituted    by OH, C₁-C₄-alkoxy or halogen, or aromatic 5- or 6-membered    heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N,    which may have 1, 2 or 3 substituents which are selected    independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷,    CN, OH, C₁-C₂-fluoroalkyl or halogen,    -   and phenyl which may have 1, 2 or 3 substituents which are        selected independently of one another from C₁-C₄-alkyl,        C₁-C₄-alkoxy, NR⁶R⁷, OH, CN, C₁-C₂-fluoroalkyl or halogen.    -   R¹ is in particular selected from optionally substituted phenyl,        halogen, OH, NR⁶R⁷, C₁-C₄-alkoxy and C₁-C₄-alkyl which is        optionally substituted by OH, C₁-C₄-alkoxy or halogen,        particularly preferably from phenyl, OH, halogen, C₁-C₂-alkoxy,        C₁-C₂-alkyl, C₁-C₂-fluoroalkyl, and specifically from phenyl,        OH, methyl, methoxy and trifluoromethyl;-   R² hydrogen, halogen, CN, OR⁵, NR⁶R⁷, SR⁸, and C₁-C₄-alkyl which is    optionally substituted by OH, C₁-C₄-alkoxy or halogen, and    specifically hydrogen;    -   Preferred compounds I among these are those in which at least        one of the radicals R¹ or R² is different from hydrogen. In        particular, the compounds I have a substituent R¹ different from        hydrogen in the 3, 4 or 6 position of the pyridone ring.-   R³ C₁-C₆-alkyl, in particular branched alkyl having 3 to 6 C atoms,    or C₃-C₆-cycloalkyl, particularly preferably tertiary alkyl having 3    to 6 C atoms and specifically tert-butyl.-   R⁴ C₁-C₆-alkyl, C₃-C₆-cycloalkyl which optionally has 1 or 2    substituents selected from chlorine and methyl, and    C₁-C₂-fluoroalkyl. In a first particularly preferred embodiment, R⁴    is C₁-C₂-fluoroalkyl or C₂-C₆-alkyl, specifically trifluoromethyl or    C₃-C₄-alkyl such as n-propyl, n-butyl, isopropyl or tert-butyl. R⁴    is very particularly preferably n-propyl or trifluoromethyl. In    another particularly preferred embodiment, R⁴ is C₃-C₆-cycloalkyl    which optionally has 1 or 2 substituents selected from chlorine and    methyl, and in particular is cyclopropyl, cyclobutyl, cyclopentyl or    1-methylcyclopropyl.-   A a four-membered hydrocarbon chain which may have 1 or 2 methyl    groups as substituents and/or a double bond, in particular    butane-1,4-diyl, 2-methylbutane-1,4-diyl,    (R)-2-methylbutane-1,4-diyl, (S)-2-methylbutane-1,4-diyl,    2-methylbut-2-ene-1,4-diyl, 3-methylbut-2-ene-1,4-diyl and    3-methylbutane-1,4-diyl, (R)-3-methylbutane-1,4-diyl,    (S)-3-methylbutane-1,4-diyl, particularly preferably    butane-1,4-diyl.

Moreover, the groups R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² preferablyhave the meanings indicated below:

-   R⁵ H, C₁-C₄-alkyl, CF₃, CHF₂ or phenyl. OR⁵ is particularly    preferably C₁-C₄-alkoxy, specifically methoxy or ethoxy,    trifluoromethoxy or phenoxy.-   R⁶ hydrogen or alkyl.-   R⁷ hydrogen, C₁-C₄-alkyl, phenyl, benzyl or a group C(O)R¹¹. In    substituents CONR⁶R⁷, preferably R⁶ is H or C₁-C₄-alkyl and    preferably R⁷ is H, C₁-C₄-alkyl or COR¹¹. CONR⁶R⁷ is particularly    preferably CONH₂, CONHCH₃, CON(CH₃)₂ or C(O)NHC(O)CH₃. In    substituents NR⁶R⁷ preferably R⁶ is H, C₁-C₄-alkyl or    phenyl-substituted C₁-C₄-alkyl and R⁷ is H, C₁-C₄-alkyl or COR¹¹.    NR⁶R⁷ is particularly preferably NH₂, NHCH₃, N(CH₃)₂, NH-benzyl or    NHCOCH₃. In substituents SO₂NR⁶R⁷, preferably R⁸ is H or C₁-C₄-alkyl    and preferably R⁷ is H, C₁-C₄-alkyl or COR¹¹. SO₂NR⁶R⁷ is    particularly preferably sulfamoyl. In the aforementioned groups, R⁶    and R⁷ may also form together with the nitrogen atom to which they    are bonded a saturated 5- or 6-membered, preferably saturated    nitrogen heterocycle which may have a further heteroatom such as N,    S or O and which may be substituted by 1, 2, 3 or 4 alkyl groups.    Examples of such heterocycles are piperidinyl, morpholinyl,    pyrrolidinyl, 4-methylpiperazinyl and 4-methylpiperidinyl.-   R⁸ H, C₁-C₄-alkyl, phenyl or benzyl. In substituents SR⁸, preferably    R⁸ is H, C₁-C₄-alkyl, phenyl or benzyl. In substituents SOR⁸,    preferably R⁸ is phenyl or C₁-C₄-alkyl. In substituents SO₂R⁸,    preferably R³ is H or C₁-C₄-alkyl. SO₂R⁸ is particularly preferably    methylsulfonyl;-   R⁹ H or C₁-C₄-alkyl. COOR⁹ is particularly preferably    C₁-C₄-alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,    n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl or    t-butoxycarbonyl;-   R¹⁰ H, C₁-C₄-alkyl or phenyl. COR¹⁰ is particularly preferably    formyl, acetyl, propionyl or benzoyl;-   R¹¹ H, C₁-C₄-alkyl or phenyl. COR¹¹ is particularly preferably    formyl, acetyl, propionyl or benzoyl;-   R¹² H or C₁-C₄-alkyl.

Particularly preferred compounds are those of the formula Ia indicatedbelow

in which R¹, R² and R⁴ have the meanings mentioned previously and inparticular those mentioned as preferred, where R¹ is preferably disposedin the 3, 4 or 5 position of the pyridinone ring. Examples of compoundsI preferred according to the invention are the compounds of the generalformula Ia in which R¹, R² and R⁴ have the meanings mentioned in eachcase in one line of table 1.

TABLE 1 R¹, R² R⁴ 1. 3-OH CF₃ 2. 4-OH CF₃ 3. 5-OH CF₃ 4. 3-CH₃ CF₃ 5.4-CH₃ CF₃ 6. 5-CH₃ CF₃ 7. 3-OCH₃ CF₃ 8. 4-OCH₃ CF₃ 9. 5-OCH₃ CF₃ 10.3-N(CH₃)₂ CF₃ 11. 4-N(CH₃)₂ CF₃ 12. 5-N(CH₃)₂ CF₃ 13. 3-Cl CF₃ 14. 4-ClCF₃ 15. 5-Cl CF₃ 16. 3-CF₃ CF₃ 17. 4-CF₃ CF₃ 18. 5-CF₃ CF₃ 19. 3-CN CF₃20. 4-CN CF₃ 21. 5-CN CF₃ 22. 3-H₃C—O—CH₂ CF₃ 23. 4-H₃C—O—CH₂ CF₃ 24.5-H₃C—O—CH₂ CF₃ 25. 6-CH₃ CF₃ 26. 4-tert-Butyl CF₃ 27. 4-Azetidin-1-ylCF₃ 28. 4-Pyrrolidin-1-yl CF₃ 29. 4-Piperidin-1-yl CF₃ 30. 4-Phenyl CF₃31. 4-(1-Methylpyrrol-2-yl) CF₃ 32. 4-(3-Pyridyl) CF₃ 33. 4-(3-Thienyl)CF₃ 34. 4-(4-Fluorophenyl) CF₃ 35. 4-(4-Pyridyl) CF₃ 36. 4-(3-Furyl) CF₃37. 4-(2-Furyl) CF₃ 38. 4-(2-Pyrrolyl) CF₃ 39. 4-(2-Thienyl) CF₃ 40.4-(Pyridazin-2-yl) CF₃ 41. 4-(4-Methylthiazol-5-yl) CF₃ 42.4-(2-Methyloxazol-4-yl) CF₃ 43. 4-(Cyclopropyl) CF₃ 44. 4-(Cyclobutyl)CF₃ 45. 4-(Cyclopentyl) CF₃ 46. 4-(Cyclohexyl) CF₃ 47. 4-(Oxan-4-yl) CF₃48. 4-(1-Methylpiperidin-4-yl) CF₃ 49. 4-OH, 5-CF₃ CF₃ 50. 4-OH, 5-CH₃CF₃ 51. 4-OH, 5-C₂H₅ CF₃ 52. 4-OH, 5-CN CF₃ 53. 4-OH, 5-F CF₃ 54. 4-OH,5-Cl CF₃ 55. 4-OH, 6-CH₃ CF₃ 56. 3-OH CHF₂ 57. 4-OH CHF₂ 58. 5-OH CHF₂59. 3-CH₃ CHF₂ 60. 4-CH₃ CHF₂ 61. 5-CH₃ CHF₂ 62. 3-OCH₃ CHF₂ 63. 4-OCH₃CHF₂ 64. 5-OCH₃ CHF₂ 65. 3-N(CH₃)₂ CHF₂ 66. 4-N(CH₃)₂ CHF₂ 67. 5-N(CH₃)₂CHF₂ 68. 3-Cl CHF₂ 69. 4-Cl CHF₂ 70. 5-Cl CHF₂ 71. 3-CF₃ CHF₂ 72. 4-CF₃CHF₂ 73. 5-CF₃ CHF₂ 74. 3-CN CHF₂ 75. 4-CN CHF₂ 76. 5-CN CHF₂ 77.3-H₃C—O—CH₂ CHF₂ 78. 4-H₃C—O—CH₂ CHF₂ 79. 5-H₃C—O—CH₂ CHF₂ 80. 6-CH₃CHF₂ 81. 4-tert-Butyl CHF₂ 82. 4-Azetidin-1-yl CHF₂ 83.4-Pyrrolidin-1-yl CHF₂ 84. 4-Piperidin-1-yl CHF₂ 85. 4-Phenyl CHF₂ 86.4-(1-Methylpyrrol-2-yl) CHF₂ 87. 4-(3-Pyridyl) CHF₂ 88. 4-(3-Thienyl)CHF₂ 89. 4-(4-Fluorophenyl) CHF₂ 90. 4-(4-Pyridyl) CHF₂ 91. 4-(3-Furyl)CHF₂ 92. 4-(2-Furyl) CHF₂ 93. 4-(2-Pyrrolyl) CHF₂ 94. 4-(2-Thienyl) CHF₂95. 4-(Pyridazin-2-yl) CHF₂ 96. 4-(4-Methylthiazol-5-yl) CHF₂ 97.4-(2-Methyloxazol-4-yl) CHF₂ 98. 4-(Cyclopropyl) CHF₂ 99. 4-(Cyclobutyl)CHF₂ 100. 4-(Cyclopentyl) CHF₂ 101. 4-(Cyclohexyl) CHF₂ 102.4-(Oxan-4-yl) CHF₂ 103. 4-(1-Methylpiperidin-4-yl) CHF₂ 104. 4-OH, 5-CF₃CHF₂ 105. 4-OH, 5-CH₃ CHF₂ 106. 4-OH, 5-C₂H₅ CHF₂ 107. 4-OH, 5-CN CHF₂108. 4-OH, 5-F CHF₂ 109. 4-OH, 5-Cl CHF₂ 110. 4-OH, 6-CH₃ CHF₂ 111. 3-OHC(CH₃)₃ 112. 4-OH C(CH₃)₃ 113. 5-OH C(CH₃)₃ 114. 3-CH₃ C(CH₃)₃ 115.4-CH₃ C(CH₃)₃ 116. 5-CH₃ C(CH₃)₃ 117. 3-OCH₃ C(CH₃)₃ 118. 4-OCH₃ C(CH₃)₃119. 5-OCH₃ C(CH₃)₃ 120. 3-N(CH₃)₂ C(CH₃)₃ 121. 4-N(CH₃)₂ C(CH₃)₃ 122.5-N(CH₃)₂ C(CH₃)₃ 123. 3-Cl C(CH₃)₃ 124. 4-Cl C(CH₃)₃ 125. 5-Cl C(CH₃)₃126. 3-CF₃ C(CH₃)₃ 127. 4-CF₃ C(CH₃)₃ 128. 5-CF₃ C(CH₃)₃ 129. 3-CNC(CH₃)₃ 130. 4-CN C(CH₃)₃ 131. 5-CN C(CH₃)₃ 132. 3-H₃C—O—CH₂ C(CH₃)₃133. 4-H₃C—O—CH₂ C(CH₃)₃ 134. 5-H₃C—O—CH₂ C(CH₃)₃ 135. 6-CH₃ C(CH₃)₃136. 4-tert-Butyl C(CH₃)₃ 137. 4-Azetidin-1-yl C(CH₃)₃ 138.4-Pyrrolidin-1-yl C(CH₃)₃ 139. 4-Piperidin-1-yl C(CH₃)₃ 140. 4-PhenylC(CH₃)₃ 141. 4-(1-Methylpyrrol-2-yl) C(CH₃)₃ 142. 4-(3-Pyridyl) C(CH₃)₃143. 4-(3-Thienyl) C(CH₃)₃ 144. 4-(4-Fluorophenyl) C(CH₃)₃ 145.4-(4-Pyridyl) C(CH₃)₃ 146. 4-(3-Furyl) C(CH₃)₃ 147. 4-(2-Furyl) C(CH₃)₃148. 4-(2-Pyrrolyl) C(CH₃)₃ 149. 4-(2-Thienyl) C(CH₃)₃ 150.4-(Pyridazin-2-yl) C(CH₃)₃ 151. 4-(4-Methylthiazol-5-yl) C(CH₃)₃ 152.4-(2-Methyloxazol-4-yl) C(CH₃)₃ 153. 4-(Cyclopropyl) C(CH₃)₃ 154.4-(Cyclobutyl) C(CH₃)₃ 155. 4-(Cyclopentyl) C(CH₃)₃ 156. 4-(Cyclohexyl)C(CH₃)₃ 157. 4-(Oxan-4-yl) C(CH₃)₃ 158. 4-(1-Methylpiperidin-4-yl)C(CH₃)₃ 159. 4-OH, 5-CF₃ C(CH₃)₃ 160. 4-OH, 5-CH₃ C(CH₃)₃ 161. 4-OH,5-C₂H₅ C(CH₃)₃ 162. 4-OH, 5-CN C(CH₃)₃ 163. 4-OH, 5-F C(CH₃)₃ 164. 4-OH,5-Cl C(CH₃)₃ 165. 4-OH, 6-CH₃ C(CH₃)₃ 166. 3-OH cyclo-C₃H₅ 167. 4-OHcyclo-C₃H₅ 168. 5-OH cyclo-C₃H₅ 169. 3-CH₃ cyclo-C₃H₅ 170. 4-CH₃cyclo-C₃H₅ 171. 5-CH₃ cyclo-C₃H₅ 172. 3-OCH₃ cyclo-C₃H₅ 173. 4-OCH₃cyclo-C₃H₅ 174. 5-OCH₃ cyclo-C₃H₅ 175. 3-N(CH₃)₂ cyclo-C₃H₅ 176.4-N(CH₃)₂ cyclo-C₃H₅ 177. 5-N(CH₃)₂ cyclo-C₄H₇ 178. 3-Cl cyclo-C₃H₅ 179.4-Cl cyclo-C₃H₅ 180. 5-Cl cyclo-C₃H₅ 181. 3-CF₃ cyclo-C₃H₅ 182. 4-CF₃cyclo-C₃H₅ 183. 5-CF₃ cyclo-C₃H₅ 184. 3-CN cyclo-C₃H₅ 185. 4-CNcyclo-C₃H₅ 186. 5-CN cyclo-C₃H₅ 187. 3-H₃C—O—CH₂ cyclo-C₃H₅ 188.4-H₃C—O—CH₂ cyclo-C₃H₅ 189. 5-H₃C—O—CH₂ cyclo-C₃H₅ 190. 6-CH₃ cyclo-C₃H₅191. 4-tert-Butyl cyclo-C₃H₅ 192. 4-Azetidin-1-yl cyclo-C₃H₅ 193.4-Pyrrolidin-1-yl cyclo-C₃H₅ 194. 4-Piperidin-1-yl cyclo-C₃H₅ 195.4-Phenyl cyclo-C₃H₅ 196. 4-(1-Methylpyrrol-2-yl) cyclo-C₃H₅ 197.4-(3-Pyridyl) cyclo-C₃H₅ 198. 4-(3-Thienyl) cyclo-C₃H₅ 199.4-(4-Fluorophenyl) cyclo-C₃H₅ 200. 4-(4-Pyridyl) cyclo-C₃H₅ 201.4-(3-Furyl) cyclo-C₃H₅ 202. 4-(2-Furyl) cyclo-C₃H₅ 203. 4-(2-Pyrrolyl)cyclo-C₃H₅ 204. 4-(2-Thienyl) cyclo-C₃H₅ 205. 4-(Pyridazin-2-yl)cyclo-C₃H₅ 206. 4-(4-Methylthiazol-5-yl) cyclo-C₃H₅ 207.4-(2-Methyloxazol-4-yl) cyclo-C₃H₅ 208. 4-(Cyclopropyl) cyclo-C₃H₅ 209.4-(Cyclobutyl) cyclo-C₃H₅ 210. 4-(Cyclopentyl) cyclo-C₃H₅ 211.4-(Cyclohexyl) cyclo-C₃H₅ 212. 4-(Oxan-4-yl) cyclo-C₃H₅ 213.4-(1-Methylpiperidin-4-yl) cyclo-C₃H₅ 214. 4-OH, 5-CF₃ cyclo-C₃H₅ 215.4-OH, 5-CH₃ cyclo-C₃H₅ 216. 4-OH, 5-C₂H₅ cyclo-C₃H₅ 217. 4-OH, 5-CNcyclo-C₃H₅ 218. 4-OH, 5-F cyclo-C₃H₅ 219. 4-OH, 5-Cl cyclo-C₃H₅ 220.4-OH, 6-CH₃ cyclo-C₃H₅ 221. 3-OH cyclo-C₄H₇ 222. 4-OH cyclo-C₄H₇ 223.5-OH cyclo-C₄H₇ 224. 3-CH₃ cyclo-C₄H₇ 225. 4-CH₃ cyclo-C₄H₇ 226. 5-CH₃cyclo-C₄H₇ 227. 3-OCH₃ cyclo-C₄H₇ 228. 4-OCH₃ cyclo-C₄H₇ 229. 5-OCH₃cyclo-C₄H₇ 230. 3-N(CH₃)₂ cyclo-C₄H₇ 231. 4-N(CH₃)₂ cyclo-C₄H₇ 232.5-N(CH₃)₂ cyclo-C₄H₇ 233. 3-Cl cyclo-C₄H₇ 234. 4-Cl cyclo-C₄H₇ 235. 5-Clcyclo-C₄H₇ 236. 3-CF₃ cyclo-C₄H₇ 237. 4-CF₃ cyclo-C₄H₇ 238. 5-CF₃cyclo-C₄H₇ 239. 3-CN cyclo-C₄H₇ 240. 4-CN cyclo-C₄H₇ 241. 5-CNcyclo-C₄H₇ 242. 3-H₃C—O—CH₂ cyclo-C₄H₇ 243. 4-H₃C—O—CH₂ cyclo-C₄H₇ 244.5-H₃C—O—CH₂ cyclo-C₄H₇ 245. 6-CH₃ cyclo-C₄H₇ 246. 4-tert-Butylcyclo-C₄H₇ 247. 4-Azetidin-1-yl cyclo-C₄H₇ 248. 4-Pyrrolidin-1-ylcyclo-C₄H₇ 249. 4-Piperidin-1-yl cyclo-C₄H₇ 250. 4-Phenyl cyclo-C₄H₇251. 4-(1-Methylpyrrol-2-yl) cyclo-C₄H₇ 252. 4-(3-Pyridyl) cyclo-C₄H₇253. 4-(3-Thienyl) cyclo-C₄H₇ 254. 4-(4-Fluorophenyl) cyclo-C₄H₇ 255.4-(4-Pyridyl) cyclo-C₄H₇ 256. 4-(3-Furyl) cyclo-C₄H₇ 257. 4-(2-Furyl)cyclo-C₄H₇ 258. 4-(2-Pyrrolyl) cyclo-C₄H₇ 259. 4-(2-Thienyl) cyclo-C₄H₇260. 4-(Pyridazin-2-yl) cyclo-C₄H₇ 261. 4-(4-Methylthiazol-5-yl)cyclo-C₄H₇ 262. 4-(2-Methyloxazol-4-yl) cyclo-C₄H₇ 263. 4-(Cyclopropyl)cyclo-C₄H₇ 264. 4-(Cyclobutyl) cyclo-C₄H₇ 265. 4-(Cyclopentyl)cyclo-C₄H₇ 266. 4-(Cyclohexyl) cyclo-C₄H₇ 267. 4-(Oxan-4-yl) cyclo-C₄H₇268. 4-(1-Methylpiperidin-4-yl) cyclo-C₄H₇ 269. 4-OH, 5-CF₃ cyclo-C₄H₇270. 4-OH, 5-CH₃ cyclo-C₄H₇ 271. 4-OH, 5-C₂H₅ cyclo-C₄H₇ 272. 4-OH, 5-CNcyclo-C₄H₇ 273. 4-OH, 5-F cyclo-C₄H₇ 274. 4-OH, 5-Cl cyclo-C₄H₇ 275.4-OH, 6-CH₃ cyclo-C₄H₇ 276. 3-OH cyclo-C₅H₉ 277. 4-OH cyclo-C₅H₉ 278.5-OH cyclo-C₅H₉ 279. 3-CH₃ cyclo-C₅H₉ 280. 4-CH₃ cyclo-C₅H₉ 281. 5-CH₃cyclo-C₅H₉ 282. 3-OCH₃ cyclo-C₅H₉ 283. 4-OCH₃ cyclo-C₅H₉ 284. 5-OCH₃cyclo-C₅H₉ 285. 3-N(CH₃)₂ cyclo-C₅H₉ 286. 4-N(CH₃)₂ cyclo-C₅H₉ 287.5-N(CH₃)₂ cyclo-C₅H₉ 288. 3-Cl cyclo-C₅H₉ 289. 4-Cl cyclo-C₅H₉ 290. 5-Clcyclo-C₅H₉ 291. 3-CF₃ cyclo-C₅H₉ 292. 4-CF₃ cyclo-C₅H₉ 293. 5-CF₃cyclo-C₅H₉ 294. 3-CN cyclo-C₅H₉ 295. 4-CN cyclo-C₅H₉ 296. 5-CNcyclo-C₅H₉ 297. 3-H₃C—O—CH₂ cyclo-C₅H₉ 298. 4-H₃C—O—CH₂ cyclo-C₅H₉ 299.5-H₃C—O—CH₂ cyclo-C₅H₉ 300. 6-CH₃ cyclo-C₅H₉ 301. 4-tert-Butylcyclo-C₅H₉ 302. 4-Azetidin-1-yl cyclo-C₅H₉ 303. 4-Pyrrolidin-1-ylcyclo-C₅H₉ 304. 4-Piperidin-1-yl cyclo-C₅H₉ 305. 4-Phenyl cyclo-C₅H₉306. 4-(1-Methylpyrrol-2-yl) cyclo-C₅H₉ 307. 4-(3-Pyridyl) cyclo-C₅H₉308. 4-(3-Thienyl) cyclo-C₅H₉ 309. 4-(4-Fluorophenyl) cyclo-C₅H₉ 310.4-(4-Pyridyl) cyclo-C₅H₉ 311. 4-(3-Furyl) cyclo-C₅H₉ 312. 4-(2-Furyl)cyclo-C₅H₉ 313. 4-(2-Pyrrolyl) cyclo-C₅H₉ 314. 4-(2-Thienyl) cyclo-C₅H₉315. 4-(Pyridazin-2-yl) cyclo-C₅H₉ 316. 4-(4-Methylthiazol-5-yl)cyclo-C₅H₉ 317. 4-(2-Methyloxazol-4-yl) cyclo-C₅H₉ 318. 4-(Cyclopropyl)cyclo-C₅H₉ 319. 4-(Cyclobutyl) cyclo-C₅H₉ 320. 4-(Cyclopentyl)cyclo-C₅H₉ 321. 4-(Cyclohexyl) cyclo-C₅H₉ 322. 4-(Oxan-4-yl) cyclo-C₅H₉323. 4-(1-Methylpiperidin-4-yl) cyclo-C₅H₉ 324. 4-OH, 5-CF₃ cyclo-C₅H₉325. 4-OH, 5-CH₃ cyclo-C₅H₉ 326. 4-OH, 5-C₂H₅ cyclo-C₅H₉ 327. 4-OH, 5-CNcyclo-C₅H₉ 328. 4-OH, 5-F cyclo-C₅H₉ 329. 4-OH, 5-Cl cyclo-C₅H₉ 330.4-OH, 6-CH₃ cyclo-C₅H₉ 331. 3-OH CH₃ 332. 4-OH CH₃ 333. 5-OH CH₃ 334.3-CH₃ CH₃ 335. 4-CH₃ CH₃ 336. 5-CH₃ CH₃ 337. 3-OCH₃ CH₃ 338. 4-OCH₃ CH₃339. 5-OCH₃ CH₃ 340. 3-N(CH₃)₂ CH₃ 341. 4-N(CH₃)₂ CH₃ 342. 5-N(CH₃)₂ CH₃343. 3-Cl CH₃ 344. 4-Cl CH₃ 345. 5-Cl CH₃ 346. 3-CF₃ CH₃ 347. 4-CF₃ CH₃348. 5-CF₃ CH₃ 349. 3-CN CH₃ 350. 4-CN CH₃ 351. 5-CN CH₃ 352.3-H₃C—O—CH₂ CH₃ 353. 4-H₃C—O—CH₂ CH₃ 354. 5-H₃C—O—CH₂ CH₃ 355. 6-CH₃ CH₃356. 4-tert-Butyl CH₃ 357. 4-Azetidin-1-yl CH₃ 358. 4-Pyrrolidin-1-ylCH₃ 359. 4-Piperidin-1-yl CH₃ 360. 4-Phenyl CH₃ 361.4-(1-Methylpyrrol-2-yl) CH₃ 362. 4-(3-Pyridyl) CH₃ 363. 4-(3-Thienyl)CH₃ 364. 4-(4-Fluorophenyl) CH₃ 365. 4-(4-Pyridyl) CH₃ 366. 4-(3-Furyl)CH₃ 367. 4-(2-Furyl) CH₃ 368. 4-(2-Pyrrolyl) CH₃ 369. 4-(2-Thienyl) CH₃370. 4-(Pyridazin-2-yl) CH₃ 371. 4-(4-Methylthiazol-5-yl) CH₃ 372.4-(2-Methyloxazol-4-yl) CH₃ 373. 4-(Cyclopropyl) CH₃ 374. 4-(Cyclobutyl)CH₃ 375. 4-(Cyclopentyl) CH₃ 376. 4-(Cyclohexyl) CH₃ 377. 4-(Oxan-4-yl)CH₃ 378. 4-(1-Methylpiperidin-4-yl) CH₃ 379. 4-OH, 5-CF₃ CH₃ 380. 4-OH,5-CH₃ CH₃ 381. 4-OH, 5-C₂H₅ CH₃ 382. 4-OH, 5-CN CH₃ 383. 4-OH, 5-F CH₃384. 4-OH, 5-Cl CH₃ 385. 4-OH, 6-CH₃ CH₃ 386. 3-OH CH(CH₃)₂ 387. 4-OHCH(CH₃)₂ 388. 5-OH CH(CH₃)₂ 389. 3-CH₃ CH(CH₃)₂ 390. 4-CH₃ CH(CH₃)₂ 391.5-CH₃ CH(CH₃)₂ 392. 3-OCH₃ CH(CH₃)₂ 393. 4-OCH₃ CH(CH₃)₂ 394. 5-OCH₃CH(CH₃)₂ 395. 3-N(CH₃)₂ CH(CH₃)₂ 396. 4-N(CH₃)₂ CH(CH₃)₂ 397. 5-N(CH₃)₂CH(CH₃)₂ 398. 3-Cl CH(CH₃)₂ 399. 4-Cl CH(CH₃)₂ 400. 5-Cl CH(CH₃)₂ 401.3-CF₃ CH(CH₃)₂ 402. 4-CF₃ CH(CH₃)₂ 403. 5-CF₃ CH(CH₃)₂ 404. 3-CNCH(CH₃)₂ 405. 4-CN CH(CH₃)₂ 406. 5-CN CH(CH₃)₂ 407. 3-H₃C—O—CH₂ CH(CH₃)₂408. 4-H₃C—O—CH₂ CH(CH₃)₂ 409. 5-H₃C—O—CH₂ CH(CH₃)₂ 410. 6-CH₃ CH(CH₃)₂411. 4-tert-Butyl CH(CH₃)₂ 412. 4-Azetidin-1-yl CH(CH₃)₂ 413.4-Pyrrolidin-1-yl CH(CH₃)₂ 414. 4-Piperidin-1-yl CH(CH₃)₂ 415. 4-PhenylCH(CH₃)₂ 416. 4-(1-Methylpyrrol-2-yl) CH(CH₃)₂ 417. 4-(3-Pyridyl)CH(CH₃)₂ 418. 4-(3-Thienyl) CH(CH₃)₂ 419. 4-(4-Fluorophenyl) CH(CH₃)₂420. 4-(4-Pyridyl) CH(CH₃)₂ 421. 4-(3-Furyl) CH(CH₃)₂ 422. 4-(2-Furyl)CH(CH₃)₂ 423. 4-(2-Pyrrolyl) CH(CH₃)₂ 424. 4-(2-Thienyl) CH(CH₃)₂ 425.4-(Pyridazin-2-yl) CH(CH₃)₂ 426. 4-(4-Methylthiazol-5-yl) CH(CH₃)₂ 427.4-(2-Methyloxazol-4-yl) CH(CH₃)₂ 428. 4-(Cyclopropyl) CH(CH₃)₂ 429.4-(Cyclobutyl) CH(CH₃)₂ 430. 4-(Cyclopentyl) CH(CH₃)₂ 431.4-(Cyclohexyl) CH(CH₃)₂ 432. 4-(Oxan-4-yl) CH(CH₃)₂ 433.4-(1-Methylpiperidin-4-yl) CH(CH₃)₂ 434. 4-OH, 5-CF₃ CH(CH₃)₂ 435. 4-OH,5-CH₃ CH(CH₃)₂ 436. 4-OH, 5-C₂H₅ CH(CH₃)₂ 437. 4-OH, 5-CN CH(CH₃)₂ 438.4-OH, 5-F CH(CH₃)₂ 439. 4-OH, 5-Cl CH(CH₃)₂ 440. 4-OH, 6-CH₃ CH(CH₃)₂441. 3-OH CH₂CH₂CH₃ 442. 4-OH CH₂CH₂CH₃ 443. 5-OH CH₂CH₂CH₃ 444. 3-CH₃CH₂CH₂CH₃ 445. 4-CH₃ CH₂CH₂CH₃ 446. 5-CH₃ CH₂CH₂CH₃ 447. 3-OCH₃CH₂CH₂CH₃ 448. 4-OCH₃ CH₂CH₂CH₃ 449. 5-OCH₃ CH₂CH₂CH₃ 450. 3-N(CH₃)₂CH₂CH₂CH₃ 451. 4-N(CH₃)₂ CH₂CH₂CH₃ 452. 5-N(CH₃)₂ CH₂CH₂CH₃ 453. 3-ClCH₂CH₂CH₃ 454. 4-Cl CH₂CH₂CH₃ 455. 5-Cl CH₂CH₂CH₃ 456. 3-CF₃ CH₂CH₂CH₃457. 4-CF₃ CH₂CH₂CH₃ 458. 5-CF₃ CH₂CH₂CH₃ 459. 3-CN CH₂CH₂CH₃ 460. 4-CNCH₂CH₂CH₃ 461. 5-CN CH₂CH₂CH₃ 462. 3-H₃C—O—CH₂ CH₂CH₂CH₃ 463.4-H₃C—O—CH₂ CH₂CH₂CH₃ 464. 5-H₃C—O—CH₂ CH₂CH₂CH₃ 465. 6-CH₃ CH₂CH₂CH₃466. 4-tert-Butyl CH₂CH₂CH₃ 467. 4-Azetidin-1-yl CH₂CH₂CH₃ 468.4-Pyrrolidin-1-yl CH₂CH₂CH₃ 469. 4-Piperidin-1-yl CH₂CH₂CH₃ 470.4-Phenyl CH₂CH₂CH₃ 471. 4-(1-Methylpyrrol-2-yl) CH₂CH₂CH₃ 472.4-(3-Pyridyl) CH₂CH₂CH₃ 473. 4-(3-Thienyl) CH₂CH₂CH₃ 474.4-(4-Fluorophenyl) CH₂CH₂CH₃ 475. 4-(4-Pyridyl) CH₂CH₂CH₃ 476.4-(3-Furyl) CH₂CH₂CH₃ 477. 4-(2-Furyl) CH₂CH₂CH₃ 478. 4-(2-Pyrrolyl)CH₂CH₂CH₃ 479. 4-(2-Thienyl) CH₂CH₂CH₃ 480. 4-(Pyridazin-2-yl) CH₂CH₂CH₃481. 4-(4-Methylthiazol-5-yl) CH₂CH₂CH₃ 482. 4-(2-Methyloxazol-4-yl)CH₂CH₂CH₃ 483. 4-(Cyclopropyl) CH₂CH₂CH₃ 484. 4-(Cyclobutyl) CH₂CH₂CH₃485. 4-(Cyclopentyl) CH₂CH₂CH₃ 486. 4-(Cyclohexyl) CH₂CH₂CH₃ 487.4-(Oxan-4-yl) CH₂CH₂CH₃ 488. 4-(1-Methylpiperidin-4-yl) CH₂CH₂CH₃ 489.4-OH, 5-CF₃ CH₂CH₂CH₃ 490. 4-OH, 5-CH₃ CH₂CH₂CH₃ 491. 4-OH, 5-C₂H₅CH₂CH₂CH₃ 492. 4-OH, 5-CN CH₂CH₂CH₃ 493. 4-OH, 5-F CH₂CH₂CH₃ 494. 4-OH,5-Cl CH₂CH₂CH₃ 495. 4-OH, 6-CH₃ CH₂CH₂CH₃

Particularly preferred compounds are additionally those of the formulaeIb, Ic, Id and Ie,

in which R¹, R² and R⁴ have the meanings mentioned previously and inparticular those mentioned as preferred, where R¹ is preferably disposedin the 3, 4 or 5 position of the pyridinone ring. Examples of compoundsI preferred according to the invention are the compounds of the generalformulae Ib, Ic, Id and Ie in which R¹, R² and R⁴ have the meaningsmentioned in each case in one line of table 1. The carbon atom whichcarries the methyl group in formulae Id and Ie may have both the S andthe R configuration. Formulae Id and Ie therefore comprise both thecompounds with uniform S or R configuration and non-racemic mixtures andracemates.

The compounds I of the invention are prepared in analogy to methodsknown from the literature. An important route to the compounds of theinvention is depicted in scheme 1.

R¹, R², R³, R and A in scheme 1 have the aforementioned meanings. L¹ andL² are nucleophilically displaceable leaving groups. Examples ofsuitable nucleophilically displaceable leaving groups are halogen,especially chlorine, bromine or iodine, alkyl- and arylsulfonate such asmesylate, tosylate. L¹ and L² are preferably different from one anotherand differ in reactivity. For example, L¹ is bromine or iodine and L² ischlorine. The reaction conditions required for the reaction correspondto the reaction conditions usual for nucleophilic substitutions.

Compounds of the general formula IV are either known from theliterature, e.g. from WO 96/02519, WO 97/25324, WO 99/02503 or from theliterature cited in these publications, or can be prepared by theprocesses described therein.

The pyridinone compounds of the formulae II are known and in some casescommercially available or can be prepared by known processes forpyridinone synthesis as described, for example, in J. Med. Chem. 16(5),1973, pp. 524-528, J. Org. Chem., 67, 2002, pp. 4304-4308, Bioorg., Med.Chem. Lett, 12, 2002, pp. 3537-3541.

In the compounds I with R¹═SH, the thiol group can be converted bystandard processes of organic chemistry into other radicals R¹. Scheme 2provides a survey.

Processes for this purpose are known to the skilled worker and compriseconversion of SH into SR⁸ by alkylation, oxidation of SR⁸ to thecorresponding SOR⁸ and SO₂R⁶ groups, oxidative degradation of SH to OHwith optional subsequent alkylation or esterification to give the groupsOR⁵, OC(O)NR⁶R⁷ or OC(O)R¹⁰.

The halogen atom in the compounds I and in the starting materials of theformula II in which R¹ is Cl, Br or I can be replaced by a C-bondedorganic radical R¹ in a transition metal-catalyzed reaction, e.g. in thepresence of elemental Pd or Pd compounds, e.g. in the manner of a Suzukireaction, of a Stille coupling, or of a Heck reaction. It is possible inparticular for compounds I and pyridones I in which R¹ is an optionallysubstituted phenyl ring to be prepared by reacting the correspondinghalogen compound I or II (R¹═Cl, Br or I) with a borate M[aryl₄B] inwhich M is a cation of an alkali metal, e.g. Na⁺, and aryl is optionallysubstituted phenyl, under Suzuki conditions (see Tetrahedron 1997, 53,14437-50). This modified Suzuki cross-coupling between a halopyridone Ior II and the borate normally takes place in aqueous solvents in thepresence of a phosphine-free Pd catalyst such as palladium(II) chlorideand in the presence of a base. Examples of suitable bases are alkalimetal hydroxides such as sodium hydroxide. The halopyridones II andborates are known from the literature.

Unless indicated otherwise, the reactions described above will generallytake place in a solvent at a temperature between room temperature andthe boiling point of the solvent used. Examples of solvents which can beused are ethers such as diethyl ether, diisopropyl ether, methyltert-butyl ether or tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dimethoxyethane, toluene, xylene, acetonitrile, ketones suchas acetone or methyl ethyl ketone, or alcohols such as methanol, ethanolor butanol.

The energy of activation necessary for the reaction can be introducedinto the reaction mixture by means of microwaves (for reaction with useof microwaves, see Tetrahedron 2001, 57, pp. 9199 et seq., pp. 9225 etseq., and generally “Microwaves in Organic Synthesis”, André Loupy(editor), Wiley-VCH 2002).

If desired, a base is present to neutralize the protons liberated duringthe reaction. Suitable bases comprise inorganic bases such as sodium orpotassium carbonate, sodium or potassium bicarbonate, also alcoholatessuch as sodium methoxide, sodium ethoxide, alkali metal hydrides such assodium hydride, organometallic compounds such as butyllithium oralkylmagnesium compounds, or organic nitrogen bases such astriethylamine or pyridine. The latter may simultaneously act as solvent.

The crude product is isolated in a conventional way, for example byfiltration, removal of the solvent by distillation or extraction fromthe reaction mixture etc. The resulting compounds can be purified in aconventional way, for example by recrystallization from a solvent,chromatography or conversion into an acid addition salt.

The acid addition salts are prepared in a conventional way by mixing thefree base with the appropriate acid, where appropriate in solution in anorganic solvent, for example a low molecular weight alcohol such asmethanol, ethanol or propanol, an ether such as methyl t-butyl ether ordiisopropyl ether, a ketone such as acetone or methyl ethyl ketone or anester such as ethyl acetate.

The inventive compounds of the formula I are in general highly selectivedopamine D₃ receptor ligands which, because of their low affinity forother receptors such as D₁ receptors, D₄ receptors, α1- and/orα2-adrenergic receptors, muscarinergic receptors, histaminic receptors,opiate receptors and, in particular, for dopamine D₂ receptors, havefewer side effects than classical neuroleptics which comprise D₂receptor antagonists.

The high affinity of the inventive compounds for D₃ receptors isreflected in very, low in vitro K_(i) values of ordinarily less than 100nM (nmol/l), frequently less than 50 nM and especially of less than 10nM. Binding affinities for D₃ receptors can for example be determinedvia the displacement of [¹²⁵I]-iodosulpiride in receptor-bindingstudies.

Particularly important according to the invention are compounds whoseselectivity K_(i)(D₂)/K_(i)(D₃) is preferably at least 10, frequently atleast 30 and particularly advantageously at least 50. Receptor-bindingstudies on D₁, D₂ and D₄ receptors can be carried out for example viathe displacement of [³H]SCH23390, [¹²⁵I]iodosulpiride and[¹²⁵I]spiperone.

The compounds can, because of their binding profile, be used for thetreatment of conditions which respond to dopamine D₃ ligands, i.e. theyare effective for the treatment of those disorders or conditions wherean influencing (modulation) of dopamine D₃ receptors leads to animprovement in the clinical condition or to cure of the disease.Examples of such conditions are disorders or conditions of the centralnervous system.

Disorders or conditions of the central nervous system mean disordersaffecting the spinal cord or, in particular, the brain. The term“disorder” in the sense according to the invention refers toabnormalities which are usually regarded as pathological states orfunctions and may reveal themselves in the form of particular signs,symptoms and/or dysfunctions. The inventive treatment may be directed atindividual disorders, i.e. abnormalities or pathological states, but itis also possible for a plurality of abnormalities, which are causallyconnected together where appropriate, to be combined into patterns, i.e.syndromes, which can be treated according to the invention.

The disorders which can be treated according to the invention include inparticular psychiatric and neurological disorders. These comprise inparticular organic disorders, symptomatic disorders included, such aspsychoses of the acute exogenous type or associated psychoses with anorganic or exogenous cause, e.g. associated with metabolic disorders,infections and endocrinopathies; endogenous psychoses such asschizophrenia and schizotypal and delusional disorders; affectivedisorders such as depressions, mania and manic/depressive states; andcombined forms of the disorders described above; neurotic and somatoformdisorders, and disorders associated with stress; dissociative disorders,e.g. deficits, clouding and splitting of consciousness and personalitydisorders; disorders of attention and waking/sleeping behavior, such asbehavioral disorders and emotional disorders starting in childhood andadolescence, e.g. hyperactivity in children, intellectual deficits,especially attention deficit disorders, disorders of memory andcognition, e.g. learning and memory impairment (impaired cognitivefunction), dementia, narcolepsy and sleeping disorders, e.g. restlesslegs syndrome; developmental disorders; anxiety states; delirium;disorders of the sex life, e.g. male impotence; eating disorders, e.g.anorexia or bulimia; addiction; and other undefined psychiatricdisorders.

The disorders which can be treated according to the invention alsoinclude parkinsonism and epilepsy and, in particular, the affectivedisorders associated therewith.

Addictive disorders include the psychological disorders and behavioraldisorders caused by the abuse of psychotropic substances such aspharmaceuticals or drugs, and other addictive disorders such as, forexample, compulsive gambling (impulse control disorders not elsewhereclassified). Examples of addictive substances are: opioids (e.g.morphine, heroin, codeine); cocaine; nicotine; alcohol; substances whichinteract with the GABA chloride channel complex, sedatives, hypnotics ortranquilizers, for example benzodiazepines; LSD; cannabinoids;psychomotor stimulants such as 3,4-methylenedioxy-N-methylamphetamine(Ecstasy); amphetamine and amphetamine-like substances such asmethylphenidate or other stimulants, including caffeine. Addictivesubstances requiring particular attention are opioids, cocaine,amphetamine or amphetamine-like substances, nicotine and alcohol.

With a view to the treatment of addictive disorders, the inventivecompounds of the formula I which are particularly preferred are thosewhich themselves have no psychotropic effect. This can also be observedin a test on rats which reduce the self-administration of psychotropicsubstances, for example cocaine, after administration of compounds whichcan be used according to the invention.

According to a further aspect of the present invention, the inventivecompounds are suitable for the treatment of disorders, the causes ofwhich can at least in part be attributed to an abnormal activity ofdopamine D₃ receptors.

According to another aspect of the present invention, the treatment isdirected in particular at those disorders which can be influenced by abinding of, preferably exogenously added, binding partners (ligands) todopamine D₃ receptors in the sense of an expedient medical treatment.

The conditions which can be treated with the inventive compounds arefrequently characterized by a progressive development, i.e. the statesdescribed above change over the course of time, the severity usuallyincreasing and, where appropriate, states possibly interchanging orother states being added to previously existing states.

The inventive compounds can be used to treat a large number of signs,symptoms and/or dysfunctions associated with the disorders of thecentral nervous system and in particular the aforementioned states.These include for example a distorted relation to reality, lack ofinsight and the ability to comply with the usual social norms anddemands of life, changes in behavior, changes in individual urges suchas hunger, sleep, thirst etc. and in mood, disorders of memory andassociation, personality changes, especially emotional lability,hallucinations, ego disturbances, incoherence of thought, ambivalence,autism, depersonalization or hallucinations, delusional ideas, staccatospeech, absence of associated movement, small-step gait, bent posture oftrunk and limbs, tremor, mask-like face, monotonous speech, depression,apathy, deficient spontaneity and irresolution, reduced associationability, anxiety, nervous agitation, stammering, social phobia, panicdisorders, withdrawal syndromes associated with dependence, expansivesyndromes, states of agitation and confusion, dysphoria, dyskineticsyndromes and tic disorders, e.g. Huntington's chorea, Gilles de laTourette syndrome, vertigo syndromes, e.g. peripheral postural,rotational and vestibular vertigo, melancholia, hysteria, hypochondriaand the like.

A treatment in the sense according to the invention includes not onlythe treatment of acute or chronic signs, symptoms and/or dysfunctionsbut also a preventive treatment (prophylaxis), in particular asrecurrence or episode prophylaxis. The treatment may be symptomatic, forexample directed at suppression of symptom. It may take placeshort-term, be directed at the medium term or may also be a long-termtreatment, for example as part of maintenance therapy.

The inventive compounds are preferably suitable for the treatment ofdisorders of the central nervous system, especially for the treatment ofaffective disorders; neurotic disorders, stress disorders and somatoformdisorders and psychoses and specifically for the treatment ofschizophrenia and depression. Owing to their high selectivity inrelation to the D₃ receptor, the inventive compounds are also for thetreatment of renal function disorders, especially of renal functiondisorders caused by diabetes mellitus (see WO 00/67847).

The inventive use of the described compounds comprises a method withinthe scope of the treatment. This entails the individual to be treated,preferably a mammal, in particular a human or agricultural or domesticanimal, being given an effective amount of one or more compounds,usually formulated in accordance with pharmaceutical and veterinarypractice. Whether such a treatment is indicated, and the form it is totake, depends on the individual case and is subject to a medicalassessment (diagnosis) which takes account of the signs, symptoms and/ordysfunctions present, the risks of developing certain signs, symptomsand/or dysfunctions, and other factors.

The treatment usually takes place by administration once or more thanonce a day, where appropriate together or alternately with other activeingredients or active ingredient-containing products, so that anindividual to be treated is given a daily dose preferably of about 0.1to 1000 mg/kg of body weight on oral administration or of about 0.1 to100 mg/kg of body weight on parenteral administration.

The invention also relates to the production of pharmaceuticalcompositions for the treatment of an individual, preferably a mammal, inparticular a human or agricultural or domestic animal. Thus, the ligandsare usually administered in the form of pharmaceutical compositionswhich comprise a pharmaceutically acceptable excipient with at least oneligand of the invention and, where appropriate, further activeingredients. These compositions can be administered for example by theoral, rectal, transdermal, subcutaneous, intravenous, intramuscular orintranasal route.

Examples of suitable pharmaceutical formulations are solidpharmaceutical forms such as oral powders, dusting powders, granules,tablets, especially film-coated tablets, pastilles, sachets, cachets,sugar-coated tablets, capsules such as hard and soft gelatin capsules,suppositories or vaginal pharmaceutical forms, semisolid pharmaceuticalforms such as ointments, creams, hydrogels, pastes or patches, andliquid pharmaceutical forms such as solutions, emulsions, especiallyoil-in-water emulsions, suspensions, for example lotions, preparationsfor injection and infusion, eye drops and ear drops. Implanted deliverydevices can also be used to administer compounds of the invention. Afurther possibility is also to use liposomes or microspheres.

The compositions are produced by mixing or diluting compounds of theinvention usually with an excipient. Excipients may be solid, semisolidor liquid materials which serve as vehicle, carrier or medium for theactive ingredient.

Suitable excipients are listed in the relevant pharmaceuticalmonographs. The formulations may additionally comprise pharmaceuticallyacceptable carriers or conventional excipients such as lubricants;wetting agents; emulsifying and suspending agents; preservatives;antioxidants; antiirritants; chelating agents; tablet-coating aids;emulsion stabilizers; film formers; gel formers; odor-masking agents;masking flavors; resins; hydrocolloids; solvents; solubilizers;neutralizers; permeation promoters; pigments; quaternary ammoniumcompounds; refatting and superfatting agents; ointment, cream or oilbases; silicone derivatives; spreading aids; stabilizers; sterilants;suppository bases; tablet excipients, such as binders, fillers,lubricants, disintegrants or coatings; propellants; desiccants;opacifiers; thickeners; waxes; plasticizers; white oils. An arrangementconcerning this is based on expert knowledge as set forth for example inFiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik undangrenzende Gebiete, 4th edition, Aulendorf: ECV-Editio-Kantor-Verlag,1996.

The following examples serve to illustrate the invention withoutlimiting it.

The nuclear magnetic resonance spectral properties (NMR) relate tochemical shifts (δ) expressed in parts per million (ppm). The relativearea for the shifts in the ¹H NMR spectrum corresponds to the number ofhydrogen atoms for a particular functional type in the molecule. Thenature of the shift in terms of multiplicity is indicated as singlet(s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet(t), broad triplet (t br.), quartet (q), quintet (quint.), multiplet(m).

I. PREPARATION EXAMPLES Example 11-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-methylpyridin-2(1H)-one1.1 1-(4-Chlorobutyl)-4-methylpyridin-2(1H)-one

A mixture of 2-hydroxy-4-methylpyridine (1.50 g, 13.75 mmol) andpotassium carbonate (1.90 g, 13.75 mmol) in 13 ml of methanol werestirred at room temperature for 15 minutes and then1-bromo-4-chlorobutane (3.54 g, 20.62 mmol) and a spatula tip ofpotassium iodide were added thereto. The reaction mixture was heated toreflux for 6 hours and then stirred at room temperature for 12 hours.Water was then added to the reaction mixture, and the aqueous mixturewas extracted with dichloromethane. Drying of the organic phase andremoval of the desiccant by filtration was followed by concentration ofthe organic phase in vacuo. Flash chromatography of resulting residue onsilica gel (eluent: CH₂Cl₂/CH₃OH: 98:2) afforded 2.0 g of1-(4-chlorobutyl)-4-methylpyridin-2(1H)-one.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.13 (1H, d), 6.37 (1H, s), 6.02 (1H,d), 3.95 (2H, t), 3.56 (2H, t), 2.17 (3H, s), 1.90 (2H, quint.), 1.83(2H, quint.).

1.21-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-methylpyridin-2(1H)-one

1-(4-Chlorobutyl)-4-methylpyridin-2(1H)-one (0.99 g, 4.96 mmol) fromExample 1.1, 2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine(1.36 g, 4.71 mmol; prepared as described in DE 19735410) andtriethylamine (1.51 g, 14.87 mmol) in 25 ml of dimethyl sulfoxide werestirred at 100° C. for 5 hours. Water was then added to the reactionmixture, and the aqueous mixture was extracted twice with tert-butylmethyl ether. The organic phase was extracted three times with asaturated aqueous sodium chloride solution and three times with a 5%aqueous citric acid solution. The aqueous phase was then made alkalineand extracted three times with tert-butyl methyl ether. The combinedorganic phases were dried over Na₂SO₄ and, after removal of thedesiccant by filtration, concentrated. The resulting oily residue (1.99g) was purified by chromatography on silica gel (eluent: CH₂Cl₂/CH₃OH:96.5:3.5), resulting in 1.29 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.15 (1H, d), 6.59 (1H, s), 6.34 (1H,s), 6.00 (1H, d), 3.92 (2H, t), 3.70 (4H, s br.), 2.50 (4H, t), 2.41(2H, t), 2.18 (3H, s), 1.80 (2H, quint.), 1.57 (2H, quint.), 1.33 (9H,s).

Example 21-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-(trifluoromethyl)pyridin-2(1H)-one2.1 1-(4-Chlorobutyl)-5-(trifluoromethyl)pyridin-2(1H)-one

1.95 g of the title compound were obtained by reacting5-(trifluoromethyl)-2-pyridinol (1.63 g, 10 mmol) with1-bromo-4-chlorobutane in analogy to Example 1.1.

ESI-MS: [M+H⁺]=254.1.

2.21-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-(trifluoromethyl)pyridin-2(1H)-one

0.39 g of the title compound was obtained in analogy to Example 1.2 byreacting 1-(4-chlorobutyl)-5-(trifluoromethyl)pyridin-2(1H)-one (0.65 g,2.56 mmol) from Example 2.1.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.66 (1H, s), 7.45 (1H, d), 6.63 (1H,d), 6.58 (1H, s), 4.00 (2H, t), 3.73 (4H, s br.), 2.51 (4H, t), 2.43(2H, t), 1.83 (2H, quint.), 1.60 (2H, quint.), 1.32 (9H, s).

Example 34-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-methyl-2-oxopyridin-1(2H)-yl)butyl]piperazin-1-iumchloride

0.74 g of the title compound was obtained by reacting1-(4-chlorobutyl)-4-methylpyridin-2(1H)-one (2.50 mmol, 0.50 g) fromExample 1.1 with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.62g, 2.38 mmol; preparation as described in DE 19735410) in analogy toExample 1.2.

ESI-MS: 427.5, [M+H⁺]=426.5, 213.8.

Example 44-(2-tert-Butyl-6-isopropylpyrimidin-4-yl)-1-[4-(4-methyl-2-oxopyridin-1(2H)-yl)butyl]piperazin-1-iumchloride

0.38 g of the title compound was obtained by reacting1-(4-chlorobutyl)-4-methylpyridin-2(1H)-one (1.25 mmol, 0.25 g) fromExample 1.1 with 2-tert-butyl-4-piperazin-1-yl-6-isopropylpyrimidine(0.31 g, 1.19 mmol; prepared as described in DE 19735410) in analogy toExample 1.2.

ESI-MS: 427.4, [M+H⁺]=426.2, 213.8.

Example 51-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-3-methoxy-1H-pyridin-2-one5.1 1-(4-Chlorobutyl)-3-methoxy-1H-pyridin-2-one

3-Methoxy-1H-pyridin-2-one (20 mmol, 2.00 g) in 100 ml ofN,N-dimethylformamide was added dropwise over the course of 10 minutesto a suspension of sodium hydride (20 mmol, 0.74 g, 60%, deoiled) inN,N-dimethylformamide (100 ml) at 10° C., and the mixture was thenstirred at room temperature for 1 hour. Subsequently,1-bromo-4-chlorobutane (20 mmol, 3.19 g) in 40 ml ofN,N-dimethylformamide was added dropwise. The reaction mixture was thenstirred at 95° C. After the reaction mixture had been concentrated, theremaining oil was suspended in diethyl ether. The resulting suspensionwas filtered and the filtrate was washed three times with water and thenthree times with a saturated aqueous sodium chloride solution. Drying ofthe organic phase over sodium sulfate was followed by removal of thedesiccant by filtration and concentration. The resulting residuecontained a mixture of O-alkylated and N-alkylated compound.Chromatography of the residue on silica gel (eluent: CH₂Cl₂/CH₃OH: 0-2%)afforded 1.75 g of the title compound.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.88 (1H, d), 6.60 (1H, d), 6.12 (1H,t), 4.02 (2H, t), 3.81 (3H, s), 3.57 (1H, t), 3.44 (1H, t), 2.02-1.72(4H, m).

5.21-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-3-methoxy-1H-pyridin-2-one

A mixture of 1-(4-chlorobutyl)-3-methoxy-1H-pyridin-2-one (0.93 mmol,0.20 g) from Example 5.1,2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.93 mmol, 0.24 g;prepared as described in DE 19735410), sodium bromide (4.64 mmol, 0.48g), ethyldiisopropylamine (9.09 mmol, 1.17 g) and N-methylpyrrolidinone(0.5 ml) was heated at 120° C. for 6 hours. The resulting suspension wasfiltered with suction and the filtrate was concentrated. The residueobtained in this way was taken up in ethyl acetate/water. The aqueousmixture was adjusted to pH 5.5 with sodium bicarbonate and the aqueousmixture was extracted several times with diethyl ether. The organicphase was then dried, the desiccant was removed by filtration, and theorganic phase was concentrated under reduced pressure. Chromatography ofthe residue on silica gel (eluent: CH₂Cl₂/CH₃OH (0-2%) afforded 0.24 gof the title compound.

ESI-MS: [M+H⁺]=442.4, 221.6.

Example 61-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-3-methoxy-1H-pyridin-2-one

0.25 g of the title compound was obtained by reacting1-(4-chlorobutyl)-3-methoxy-1H-pyridin-2-one (0.93 mmol, 0.20 g) fromExample 5.1 with2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (0.93 mmol,0.27 g; prepared as described in DE 19735410) in analogy to Example 5.2.

ESI-MS: [M+H⁺]=468.2;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.27 (1H, d), 6.80 (1H, d), 6.15 (1H,t), 4.66 (2H, br.), 3.90 (2H, t), 3.57-3.36 (4H, m), 3.17-2.95 (4H, m),1.64 (4H, m sym.), 1.29 (9H, s).

Example 71-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-3-methyl-1H-pyridin-2-one7.1 1-(4-Chlorobutyl)-3-methyl-1H-pyridin-2-one

1.98 g of the title compound were obtained by reacting3-methyl-1H-pyridin-2-one (17.96 mmol, 2.00 g) with1-bromo-4-chlorobutane in analogy to Example 1.1.

ESI-MS: [M+H⁺]=200.05;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.19 (1H, d), 7.13 (1H, d), 6.10 (1H,t), 3.99 (2H, t), 3.58 (2H, t), 2.16 (3H, s), 2.05-1.75 (4H, m).

7.21-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-3-methyl-1H-pyridin-2-one

0.19 g of the title compound was obtained by reacting1-(4-chlorobutyl)-3-methyl-1H-pyridin-2-one (1.00 mmol, 0.20 g) fromExample 7.1 with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (1.00mmol, 0.26 g; prepared as described in DE 19735410) in analogy toExample 5.2.

ESI-MS: [M+H⁺]=426.4, 213.8.

Example 84-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-chloro-2-oxo-2H-pyridin-1-yl)butyl]-piperazineas hydrochloride 8.1 4-Chloro-1-(4-chlorobutyl)-1H-pyridin-2-one

0.20 g of the title compound was obtained by reacting4-chloropyridin-2-ol (1.54 mmol, 0.20 g) with 1-bromo-4-chlorobutane inanalogy to Example 1.1.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.20 (1H, d), 6.60 (1H, s), 6.20 (1H,d), 3.94 (2H, t), 3.58 (2H, t), 1.90 (2H, quint.), 1.81 (2H, quint.).

8.24-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-chloro-2-oxo-2H-pyridin-1-yl)butyl]-piperazinehydrochloride

0.16 g of the title compound was obtained by reacting4-chloro-1-(4-chlorobutyl)-1H-pyridin-2-one (0.45 mmol, 0.10 g) fromExample 8.1 with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.43mmol, 0.11 g; prepared as described in DE 19735410) in analogy toExample 5.2.

ESI-MS: 448.2, 446.3, 224.6, 223.6;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.20 (1H, d), 6.60 (1H, s), 6.18 (1H,d), 6.12 (1H, s), 3.95 (2H, t), 3.60 (4H, s br.), 2.60-2.33 (8H, mincluding 2.53 (2H, t), 2.40 (2H, t)), 1.83-1.49 (6H, m), 1.33 (9H, s),0.97 (3H, t).

Example 94-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-chloro-2-oxo-2H-pyridin-1-yl)butyl]piperazineas hydrochloride

0.12 g of the title compound was obtained by reacting4-chloro-1-(4-chlorobutyl)-1H-pyridin-2-one (0.45 mmol, 0.10 g) fromExample 8.1 with2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (0.43 mmol,0.11 g; prepared as described in DE 19735410) in analogy to Example 5.2.

ESI-MS: 474.2, 472.2, 237.4, 236.6;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.20 (1H, d), 6.60 (1H, s), 6.58 (1H,s), 6.19 (1H, d), 3.94 (2H, t), 3.68 (4H, s br.), 2.47 (2H, t), 2.39(2H, t), 1.77 (2H, quint.), 1.65 (2H+H₂O, quint.), 1.33 (9H, s).

Example 101-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-1H-pyridin-2-one10.1 1-(4-Chlorobutyl)-4-hydroxy-1H-pyridin-2-one

1.30 g of the title compound were obtained by reacting4-hydroxy-1H-pyridin-2-one (18.00 mmol, 2.00 g) with1-bromo-4-chlorobutane in analogy to Example 1.1.

10.21-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-1H-pyridin-2-one

0.40 g of the title compound was obtained by reacting1-(4-chlorobutyl)-4-hydroxy-1H-pyridin-2-one (2.48 mmol, 0.50 g) fromExample 10.1 with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (2.48mmol, 0.65 g; prepared as described in DE 19735410) in analogy toExample 5.2.

ESI-MS: [M+H⁺]=428.4, 214.6;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 11.93 (1H, s br.), 7.17 (1H, d), 6.12(1H, s), 5.95 (1H, d), 5.87 (1H, s), 3.97 (2H, t), 3.62 (4H, s br.),2.63-2.36 (8H, m), 1.81 (2H, quint.), 1.66 (4H+H₂O, quint.), 1.33 (9H,s), 0.96 (3H, t).

Example 111-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-3-methyl-1H-pyridin-2-one

0.34 g of the title compound was obtained by reacting1-(4-chlorobutyl)-3-methyl-1H-pyridin-2-one (1.50 mmol, 0.30 g) fromExample 7.1 with2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (1.53 mmol,0.44 g; prepared as described in DE 19735410) in analogy to Example 5.2.

ESI-MS: [M+H⁺]=452.2, 226.6;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.50 (1H, d), 7.27 (1H, d), 7.03 (1H,s), 6.11 (1H, t), 3.87 (2H, t), 3.68 (4H, s br.), 2.57-2.35 (6H, mincluding 2.36 (2H, t)), 1.98 (3H, s), 1.62 (2H, quint.), 1.43 (2H,quint.), 1.25 (9H, s).

Example 121-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-1H-pyridin-2-one

0.30 g of the title compound was obtained by reacting1-(4-chlorobutyl)-4-hydroxy-1H-pyridin-2-one (1.24 mmol, 0.25 g) fromExample 10.1 with2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (1.24 mmol,0.36 g; prepared as described in DE 19735410) in analogy to Example 5.2.

ESI-MS: [M+H⁺]=454.2, 227.6;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.04 (1H, s br.), 7.17 (1H, d), 6.58(1H, s), 5.95 (1H, d), 5.86 (1H, s), 3.99 (2H, t), 3.71 (4H, s br.),2.52 (4H, s br.), 2.43 (2H, t), 1.82 (2H, quint.), 1.77-1.51 (2H+H₂O,m), 1.35 (9H, s).

Example 131-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-3-trifluoromethyl-1H-pyridin-2-one13.1 1-(4-Chlorobutyl)-3-trifluoromethyl-1H-pyridin-2-one

1.10 g of the title compound were obtained by reacting3-trifluoromethyl-1H-pyridin-2-one (6.13 mmol, 1.00 g) with1-bromo-4-chlorobutane in analogy to Example 1.1.

ESI-MS (N-alk.): [M+H⁺]=254.1;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.73 (1H, d), 7.47 (1H, d), 6.24 (1H,t), 4.03 (2H, t), 3.60 (2H, t), 1.95 (2H, q), 1.82 (2H, q).

ESI-MS (O-alk.): [M+Na⁺]=276.1, 256.1, [M+H⁺]=254.1.

13.21-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-3-trifluoromethyl-1H-pyridin-2-one

0.17 g of the title compound was obtained by reacting1-(4-chlorobutyl)-3-trifluoromethyl-1H-pyridin-2-one (0.59 mmol, 0.15 g)from Example 13.1 with2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (0.59 mmol,0.17 g; prepared as described in DE 19735410) in analogy to Example 5.2.

ESI-MS: [M+H⁺]=506.2, 253.6;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.75 (1H, d), 7.50 (1H, d), 6.68 (1H,s), 6.22 (1H, t), 4.01 (2H, t), 3.68 (4H, s br.), 2.51 (4H, s br.), 2.43(2H, t), 1.84 (2H, quint.), 1.72-1.46 (2H+H₂O, s br.), 1.33 (9H, s).

Example 141-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-3-trifluoromethyl-1H-pyridin-2-one

0.15 g of the title compound was obtained by reacting1-(4-chlorobutyl)-3-trifluoromethyl-1H-pyridin-2-one (0.59 mmol, 0.15 g)from Example 13.1 with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine(0.59 mmol, 0.16 g; prepared as described in DE 19735410) in analogy toExample 5.2.

ESI-MS: [M+H⁺]=480.2, 240.6;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.04 (1H, d), 7.91 (1H, d), 6.43 (1H,s), 6.35 (1H, t), 3.97 (2H, t), 3.57 (4H, s br.), 2.56-2.27 (6H, mincluding 2.33 (2H, t)), 1.74-1.55 (4H, m), 1.45 (2H, quint.), 1.25 (9H,s), 0.90 (3H, t).

Example 154-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(2-oxo-4-trifluoromethyl-2H-pyridin-1-yl)butyl]piperazineas fumarate 15.1 1-(4-Chlorobutyl)-4-trifluoromethyl-1H-pyridin-2-one

The title compound was obtained in a yield of 0.45 g by reacting4-trifluoromethyl-1H-pyridin-2-one (3.07 mmol, 0.50 g) with1-bromo-4-chlorobutane in analogy to the preparation method from Example1.1.

15.24-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(2-oxo-4-trifluoromethyl-2H-pyridin-1-yl)butyl]-piperazineas fumarate

The title compound was obtained in a yield of 0.24 g by reacting1-(4-chlorobutyl)-4-trifluoromethyl-1H-pyridin-2-one (0.63 mmol, 0.16 g)with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.60 mmol, 0.16g, preparation according to DE 19735410) in analogy to the preparationmethod from Example 5.2.

ESI-MS: [M+H⁺]=480.25, 240.65;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.96 (1H, d), 6.76 (1H, s), 6.47 (1H,m), 6.44 (1H, s), 3.96 (2H, t), 3.56 (4H, s), 2.58-2.23 (8H, m),1.74-1.38 (6H, m), 1.25 (9H, s), 0.89 (3H, t).

Example 164-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-trifluoromethyl-2H-pyridin-1-yl)butyl]piperazineas fumarate

The title compound was obtained in a yield of 0.12 g by reacting1-(4-chlorobutyl)-4-trifluoromethyl-1H-pyridin-2-one (0.63 mmol, 0.16 g)with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.60mmol, 0.17 g, preparation according to DE 19735410) in analogy to thepreparation method in Example 1.2.

ESI-MS: [M+Na⁺]=528.2, 507.2, [M+H⁺]=506.1, 253.6;

Example 174-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(5-chloro-2-oxo-2H-pyridin-1-yl)butyl]-piperazineas fumarate 17.1: 5-Chloro-1-(4-chlorobutyl)-1H-pyridin-2-one

1.63 g of the title compound were obtained by reacting5-chloro-1H-pyridin-2-one (15.44 mmol, 2.00 g) with1-bromo-4-chlorobutane in analogy to Example 1.1.

ESI-MS: [M+H⁺]=221.9, 220.9, 219.9;

17.24-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(5-chloro-2-oxo-2H-pyridin-1-yl)butyl]-piperazineas fumarate

obtained in a yield of 0.35 g by reacting5-chloro-1-(4-chlorobutyl)-1H-pyridin-2-one (0.91 mmol, 0.20 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.82 mmol, 0.21 g,preparation according to DE 19735410) in analogy to the method fromExample 1.2.

ESI-MS: 448.2, [M+H⁺]=446.3, 244.4, 223.6;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.96 (1H, d), 7.46 (1H, dd),6.46-6.35 (2H, m), 3.86 (2H, t), 3.58 (4H, s br.), 2.45 (6H, s br.),1.63 (4H, sext.), 1.43 (2H, quint.), 1.24 (9H, s), 0.90 (3H, t).

Example 184-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(5-chloro-2-oxo-2H-pyridin-1-yl)butyl]piperazineas fumarate

The title compound was obtained in a yield of 0.23 g by reacting5-chloro-1-(4-chlorobutyl)-1H-pyridin-2-one (0.91 mmol, 0.20 g) and2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.82 mmol,0.24 g, preparation according to DE 19735410 in analogy to the methodfrom Example 1.2.

ESI-MS: 474.1, [M+H⁺]=472.1, 237.4, 236.6;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm): 7.97 (1H, s), 7.44 (1H, d), 7.04 (1H,s), 6.41 (1H, d), 3.86 (2H, t), 3.70 (4H, s br.), 2.44 (4H, m sym.),2.34 (2H, t), 1.65 (2H, quint.), 1.44 (2H, quint.), 1.28 (9H, s).

Example 191-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-phenyl-1H-pyridin-2-one19.1: 1-(4-Chlorobutyl)-4-phenyl-1H-pyridin-2-one

34 mg of the title compound were obtained by reacting4-phenyl-1H-pyridin-2-one (0.41 mmol, 71.0 mg, prepared from4-chloro-1H-pyridin-2-one according to Tetrahedron 1997, 53, pp.14437-50) with 1-bromo-4-chlorobutane in analogy to Example 1.1.

ESI-MS: 202.1, [M+H⁺]=200.1;

19.2:1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-phenyl-1H-pyridin-2-one

The title compound was obtained in a yield of 12 mg by reacting1-(4-chlorobutyl)-4-phenyl-1H-pyridin-2-one (0.13 mmol, 34.0 mg) with2-tert-butyl-4-piperazin-1-yltrifluoromethylpyrimidine (0.13 mmol, 37.5mg, preparation according to DE 19735410) in analogy to the method fromExample 1.2.

ESI-MS: [M+Na⁺]=536.2, 515.2, [M+H⁺]=514.2, 257.6;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.77 (1H, d), 7.72 (2H, d), 7.53-7.41(3H, m), 7.03 (1H, s br.), 6.66 (1H, s), 6.58 (1H, d), 3.93 (2H, t),3.70 (4H, s br.), 2.41 (4H, s br.), 2.33 (2H, m), 1.68 (2H, quint.),1.48 (2H, m), 1.27 (9H, s).

Example 204-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(6-methyl-2-oxo-2H-pyridin-1-yl)butyl]-piperazineas fumarate 20.1 1-(4-Chlorobutyl)-6-methyl-1H-pyridin-2-one

0.40 g of the title compound was obtained by reacting6-methyl-1H-pyridin-2-one (18.33 mmol, 2.00 g) with1-bromo-4-chlorobutane in analogy to Example 1.1.

ESI-MS: 202.1, [M+H⁺]=200.1;

20.24-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(6-methyl-2-oxo-2H-pyridin-1-yl)-butyl]-piperazineas fumarate

The title compound was obtained in a yield of 0.18 g by reacting1-(4-chlorobutyl)-6-methyl-1H-pyridin-2-one (0.75 mmol, 0.15 mg) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.67 mmol, 0.18 g,preparation according to DE 19735410) in analogy to the method fromExample 1.2.

ESI-MS: 427.4, [M+H⁺]=426.4, 213.6;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm): 7.24 (1H, m sym.), 6.43 (1H, s), 6.21(1H, d), 6.06 (1H, d), 3.96 (2H, t), 3.59 (4H, s br.), 2.47 (8H, m),2.37 (3H, s), 1.66-1.49 (6H, m), 1.27 (9H, s), 0.90 (3H, t).

Example 214-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(6-methyl-2-oxo-2H-pyridin-1-yl)butyl]piperazineas fumarate

The title compound was obtained in a yield of 0.24 g by reacting1-(4-chlorobutyl)-6-methyl-1H-pyridin-2-one 0.75 mmol, 0.15 mg) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.68 mmol,0.19 g, preparation according to DE 19735410) in analogy to the methodfrom Example 1.2.

ESI-MS: [M+H⁺]=452.2, 226.6;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm): 7.23 (1H, m sym.), 7.03 (1H, s), 6.21(1H, d), 6.08 (1H, d), 3.96 (2H, t), 3.72 (4H, s br.), 2.46 (4H, m),2.41-2.34 (5H, m), 1.59 (2H, quint.), 1.52 (2H, quint.), 1.28 (9H, s).

II EXAMPLES OF PHARMACEUTICAL ADMINISTRATION FORMS

Tablets Tablets of the following composition are compressed in a tabletpress in a conventional way: 40 mg of substance of example 2 120 mg ofcorn starch 13.5 mg of gelatin 45 mg of lactose 2.25 mg of Aerosil ®(chemically pure silica in submicroscopically fine distribution) 6.75 mgof potato starch (as 6% strength paste) Sugar-coated tablets 20 mg ofsubstance of example 2 60 mg of core composition 70 mg of sugar-coatingcomposition

The core composition consists of 9 parts of corn starch, 3 parts oflactose and 1 part of vinylpyrrolidone/vinyl acetate 60:40 copolymer.The sugar-coating composition consists of 5 parts of sucrose, 2 parts ofcorn starch, 2 parts of calcium carbonate and 1 part of talc. Thesugar-coated tablets produced in this way are subsequently provided withan enteric coating.

III. BIOLOGICAL INVESTIGATIONS Receptor Binding Studies

The substance to be tested was dissolved either in methanol/Chremophor®(BASF-AG) or in dimethyl sulfoxide and then diluted with water to thedesired concentration.

III.1 Dopamine D₃ Receptor:

The mixture (0.250 ml) is composed of membranes from ˜10⁶ HEK-293 cellswith stably expressed human dopamine D₃ receptors, 0.1 nM[¹²⁵I]-iodosulpiride and incubation buffer (total binding) or withadditional test substance (inhibition plot) or 1 μM spiperone(nonspecific binding). Triplicate mixtures were carried out.

The incubation buffer contained 50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mMCaCl₂, 2 mM MgCl₂ and 0.1% bovine serum albumin, 10 μM quinolone, 0.1%ascorbic acid (prepared fresh each day). The buffer was adjusted to pH7.4 with HCl.

III.2 Dopamine D_(2L) Receptor:

The mixture (1 ml) was composed of membranes from ˜10⁶ HEK-293 cellswith stably expressed human dopamine D_(2L) receptors (long isoform) and0.01 nM [¹²⁵I]-iodospiperone and incubation buffer (total binding) orwith additional test substance (inhibition plot) or 1 μM haloperidol(nonspecific binding). Triplicate mixtures were carried out.

The incubation buffer contained 50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mMCaCl₂, 2 mM MgCl₂ and 0.1% bovine serum albumin. The buffer was adjustedto pH 7.4 with HCl.

III.3 Measurement and Evaluation:

After incubation at 25° C. for 60 minutes, the mixtures were filteredunder vacuum through Whatman GF/B glass fiber filters using a cellharvester. The filters were transferred by a filter transfer system intoscintillation vials. After addition of 4 ml of Ultima Gold® (Packard),the samples were shaken for one hour and then the radioactivity wascounted in a beta counter (Packard, Tricarb 2000 or 2200CA). The cpvalues were converted into dpm by means of a standard quench series withthe aid of the instrument's own program.

Evaluation of the inhibition plots took place by iterative nonlinearregression analysis using the Statistical Analysis System (SAS) similarto the “LIGAND” program described by Munson and Rodbard.

In these assays, the inventive compounds show very good affinities forthe D₃ receptor (<100 nM, frequently <50 nM and in particular >10 nM)and bind selectively to the D₃ receptor.

The results of the binding assays are indicated in table 2.

TABLE 2 Example K_(i) (D₃) [nM] Selectivity vs. D₂L* 1 0.76 82 3 0.84137 5 1.20 51 6 2.20 74 7 1.25 129 11 2.31 74 19 7.89 63*K_(i)(D_(2L))/K_(i)(D₃)

1. A pyridin-2-one compound of the formula I

in which A is a 4- to 6-membered hydrocarbon chain which may have 1 or 2methyl groups as substituents, in which 1 or 2 carbon atoms may bereplaced by oxygen, a carbonyl group or sulfur, and in which thehydrocarbon chain may have a double bond or a triple bond; R¹, R² areindependently of one another hydrogen, CN, NO₂, halogen, OR⁵, NR⁶R⁷,C(O)NR⁶R⁷, O—C(O)NR⁶R⁷, SR⁸, SOR⁸, SO₂R⁸, SO₂NR⁶R⁷, COOR⁹, O—C(O)R¹⁰,COR¹⁰, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₂-C₆-haloalkenyl, C₃-C₆-cycloalkyl, 4- to 6-membered heterocyclylhaving 1, 2 or 3 heteroatoms selected from O, S and N, which may have 1,2 or 3 substituents which are selected independently of one another fromC₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, CN, OH, C₁-C₂-fluoroalkyl or halogen,phenyl which may have 1, 2 or 3 substituents which are selectedindependently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, OH,CN, C₁-C₂-fluoroalkyl or halogen, C₁-C₆-alkyl which has a substituentwhich is selected from OR⁵, NR⁶R⁷, C(O)NR⁶R⁷, O—C(O)NR⁶R⁷, SR⁸, SOR⁸,SO₂R⁸, SO₂NR⁶R⁷, COOR⁹, O—C(O)R¹⁰, COR¹⁰, C₃-C₆-cycloalkyl, 5- or6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, Sand N, and phenyl, where phenyl and heterocyclyl may have 1, 2 or 3substituents which are selected independently of one another fromC₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, CN, OH, C₁-C₂-fluoroalkyl or halogen,C₂-C₆-alkenyl which has a substituent selected from OR⁵, NR⁶R⁷,C(O)NR⁶R⁷, O—C(O)NR⁶R⁷, SR⁸, SOR⁸, SO₂R⁸, SO₂NR⁶R⁷, COOR⁹, O—C(O)R¹⁰,COR¹⁰, C₃-C₆-cycloalkyl, 5- or 6-membered heterocyclyl having 1, 2 or 3heteroatoms selected from O, S and N, and phenyl, where phenyl andheterocyclyl in turn may have 1, 2 or 3 substituents which are selectedindependently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, OH,CN, C₁-C₂-fluoroalkyl or halogen; R³, R⁴ are independently of oneanother OR⁵, NR⁶R⁷, CN, C₁-C₆-alkyl which is optionally substituted oneor more times by OH, C₁-C₄-alkoxy, halogen or phenyl which in turn mayhave 1, 2 or 3 substituents selected from C₁-C₄-alkyl, C₁-C₄-alkoxy,NR⁶R⁷, OH, CN, C₁-C₂-fluoroalkyl or halogen, or C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₄-C₁₀-bicycloalkyl,C₆-C₁₀-tricycloalkyl, where the last 5 groups mentioned may optionallybe substituted one or more times by halogen or C₁-C₄-alkyl, or halogen,CN, C₁-C₄-alkoxy, 5- or 6-membered heterocyclyl having 1, 2 or 3heteroatoms selected from O, S and N, and phenyl, where phenyl andheterocyclyl may optionally have 1, 2 or 3 substituents which areselected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy,NR⁶R⁷, CN, C₁-C₂,-fluoroalkyl and halogen; R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰are independently of one another H, C₁-C₆-alkyl which is optionallysubstituted by OH, C₁-C₄-alkoxy or phenyl which in turn may have 1, 2 or3 substituents selected from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, OH, CN,C₁-C₂-fluoroalkyl or halogen, or C₁-C₆-haloalkyl or phenyl which in turnmay have 1, 2 or 3 substituents selected from C₁-C₄-alkyl, C₁-C₄-alkoxy,NR⁶R⁷, OH, CN, C₁-C₂-fluoroalkyl or halogen, where R⁷ may also be aCOR¹¹ group, and where R⁶ with R⁷ may also, together with the nitrogento which they are bonded, form a 4-, 5- or 6-membered, saturated orunsaturated heterocycle which may have a further heteroatom selectedfrom O, S and NR¹² as ring member, where R¹² is hydrogen or C₁-C₄-alkyl,and which may be substituted by 1, 2, 3 or 4 alkyl groups; and R¹¹ ishydrogen, C₁-C₄-alkyl or phenyl which is optionally substituted by 1, 2or 3 radicals which are selected independently of one another fromC₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, CN, C₁-C₂-fluoroalkyl or halogen; andthe tautomers of the compound I, the physiologically acceptable salts ofthe compound I and the physiologically acceptable salts of the tautomersof the compound I.
 2. A pyridin-2-one compound according to claim 1, inwhich R³ is C₁-C₆-alkyl, and R⁴ is selected from C₁-C₆-alkyl,C₃-C₆-cycloalkyl which optionally has 1 or 2 substituents selected fromchlorine and methyl, and C₁-C₂-fluoroalkyl.
 3. A pyridin-2-one compoundaccording to claim 2, in which R³ is branched alkyl having 3, 4 or 5 Catoms or is C₃-C₆-cycloalkyl.
 4. A pyridin-2-one compound according toclaim 2, in which R⁴ is trifluoromethyl or C₃-C₄-alkyl.
 5. Apyridin-2-one compound according to claim 2, in which R⁴ is cyclopropyl,cyclobutyl, cyclopentyl or 1-methylcyclopropyl.
 6. A pyridin-2-onecompound according to claim 1, in which at least one of the radicals R¹or R² is different from hydrogen.
 7. A pyridin-2-one compound accordingto claim 6, in which R¹ is selected from halogen, OR⁵, NR⁶R⁷,C₁-C₄-alkyl which is optionally substituted by OH, C₁-C₄-alkoxy orhalogen, or aromatic 5- or 6-membered heterocyclyl having 1, 2 or 3heteroatoms selected from O, S and N, which may have 1, 2 or 3substituents which are selected independently of one another fromC₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, CN, OH, C₁-C₂-fluoroalkyl or halogen,and phenyl which may have 1, 2 or 3 substituents which are selectedindependently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁶R⁷, OH,CN, C₁-C₂-fluoroalkyl or halogen.
 8. A pyridin-2-one compound accordingto claim 7, in which R¹ is selected from phenyl, OH, chlorine, methyl,methoxy and trifluoromethyl.
 9. A pyridin-2-one compound according toclaim 1, in which R² is hydrogen.
 10. A pyridin-2-one compound accordingto claim 1, in which A is butane-1,4-diyl.
 11. A pharmaceuticalcomposition comprising at least one compound according to claim 1 and/orsalt thereof, optionally together with physiologically acceptablecarriers and/or excipients.
 12. A method for treating a D3 receptorrelated condition comprising administering an effective amount of atleast one compound of claim 1 to a subject in need thereof, wherein thecondition is selected from the group consisting of Parkinson's disease,anxiety, schizophrenia, and depression.